Fluorescence resonance energy transfer (FRET) is the transfer of photon energy from an excited fluorophore (the donor) to another fluorophore (the acceptor) without the emission of a photon, when the donor and acceptor molecules are in close proximity to each other. FRET enables the determination of the relative proximity of the molecules, for investigating, for example, molecular interactions between two protein partners, structural changes within one molecule, and ion concentrations. Fluorescent proteins (FPs) can be genetically fused to proteins of interest and expressed in cells. FP pairs useful for performing FRET measurements in living cells include cyan fluorescent protein (CFP) as the donor, and yellow fluorescent protein (YFP) as the acceptor, because the emission spectrum of CFP partially overlaps the excitation spectrum of YFP.
U.S. Pat. No. 3,837,339 to Aisenberg et al., which is incorporated herein by reference, describes techniques for monitoring blood glucose levels, including an implantable glucose diffusion-limited fuel cell. The output current of the fuel cell is proportional to the glucose concentration of the body fluid electrolyte and is therefore directly indicative of the blood glucose level. This information is telemetered to an external receiver which generates an alarm signal whenever the fuel cell output current exceeds or falls below a predetermined current magnitude which represents a normal blood glucose level. Valve means are actuated in response to the telemetered information to supply glucose or insulin to the monitored living body.
U.S. Pat. No. 3,861,397 to Rao et al., which is incorporated herein by reference, describes an implantable fuel cell that uses an oxidizable body substance, preferably glucose, as well as oxygen from the body fluids.
U.S. Pat. No. 4,140,963 to Rao et al., which is incorporated herein by reference, describes a device for measuring blood sugar levels, including an electrochemical glucose cell that produces an electrical signal corresponding to the sugar concentration. The glucose cell produces in conjunction with a sugar solution (as electrolyte) an electrical signal which represents a measure of the present sugar concentration value. The cell can be operated, for example, by an outer source of current, a battery, or a fuel cell, for example a glucose-oxygen cell. The cell itself can also provide its own current; it may be constructed, for example, as a glucose-oxygen-fuel cell or as a glucose/silver/silver-chloride cell.
U.S. Pat. No. 3,837,922 to Ng et al., which is incorporated herein by reference, describes an implantable fuel cell power source for an artificial heart or pacemaker device which utilizes blood carbohydrates as the anode fuel. The cathode of the implantable fuel cell is an oxygen utilizing cathode, and may be air breathing, for example, following being ventilated through a percutaneous airway by a balloon system. The anode is separated from the whole venous blood by a thin, porous membrane capable of passing a blood ultra-filtrate containing the oxidizable organics.
U.S. Pat. No. 3,774,243 to Ng et al., which is incorporated herein by reference, describes an implantable hybrid power system for artificial hearts or pacemakers, which includes a fuel cell assembly air-breathing cathode assembly. A storage battery is combined with a fuel cell for peak power requirements and for more nearly steady-state fuel cell operation. The fuel cell may have either an external anode fuel source, such as hydrogen or hydrazine, or utilize blood carbohydrates, such as glucose. Electrical output from the power system is used to power any desired type of artificial heart or pacemaker device.
U.S. Pat. No. 6,294,281 and US Patent Application Publication 2002/0025469 to Heller, which are incorporated herein by reference, describe a fuel cell having an anode and a cathode, with an anode enzyme disposed on the anode and a cathode enzyme disposed on the cathode. The fuel cell typically uses as fuel compounds available in a biological system. The fuel for the operation of the fuel cell may be provided by compounds in blood, sap, and other biological fluids or solids. Such compounds may include, for example, sugars, alcohols, carboxylic acids, carbohydrates, starches, cellulose, and dissolved or complexed oxygen (e.g., oxygen complexed with a biomolecule such as hemoglobin or myoglobin). Examples of compounds for electroreduction or electrooxidation in the operation of a fuel cell in an animal include glucose or lactate at the anode and oxygen, dissolved as molecular oxygen or bound in hemoglobin or myoglobin, at the cathode.
US Patent Application Publication 2004/0091757 to Wang et al., which is incorporated herein by reference, describes an implantable fuel cell assembly containing a device for converting fat to glycerol and fatty acid, a device for converting glycerol to hydrogen, a device for converting fatty acid to hydrogen, a device for converting a bodily fluid to a gas selected from the group consisting of hydrogen, oxygen, and mixtures thereof, and a fuel cell for producing electricity from hydrogen and oxygen.
U.S. Pat. No. 5,660,940 to Larsson et al., which is incorporated herein by reference, describes a method for producing electric energy in a biofuel-powered fuel cell, the metal in the first acid metallic salt solution forming a redox pair having a normal potential between −0.1 and 0.7 V and the metal in the second acid metallic salt solution forming a redox pair having a normal potential between 0.7 and 1.3 V, both metals preferably being vanadium which forms the redox pairs vanadium (IV)/(III) and vanadium (V)/(IV), respectively.
U.S. Pat. No. 4,578,323 to Hertl et al., which is incorporated herein by reference, describes a fuel cell which produces electricity from the anaerobic oxidation of hydroxylic compounds, e.g. alcohols and sugars, in the presence of a quinone. For applications in which the fuel used has a greater affinity for its electrons than the quinone compound in its ground state, the oxidation half cell mixture must be irradiated with light energy.
U.S. Pat. Nos. 5,368,028 and 5,101,814 to Palti, which are incorporated herein by reference, describe methods and apparatus for monitoring blood glucose levels by implanting glucose sensitive living cells, which are enclosed in a membrane permeable to glucose but impermeable to immune system cells, inside a patient. Cells that produce detectable electrical activity in response to changes in blood glucose levels are used in the apparatus along with sensors for detecting the electrical signals, as a means for detecting blood glucose levels. Human beta cells from the islets of Langerhans of the pancreas, sensor cells in taste buds, and alpha cells from the pancreas are discussed as appropriate glucose sensitive cells.
U.S. Pat. Nos. 6,091,974 and 5,529,066 to Palti, which are incorporated herein by reference, describe a capsule for encapsulating implantable cells for improving the detectability of electrical signals generated by the cells. The capsule includes a low-conductivity (high electrical resistance) membrane and a semi-permeable (low electrical resistance) membrane. The low-conductivity membrane seals around the circumference of the cell mass between the electrical poles of the capsule, and further extends for increasing the electrical resistance between the poles. The semi-permeable membrane enables nutrients and waste materials to flow to and from the cell mass. The semi-permeable membrane encloses at least one of the poles of the cell mass, and cooperates with the low-conductivity membrane to completely enclose the cell mass. The low-conductivity membrane may enclose one of the poles, if desired. Electrodes are used to detect the electrical signals from the cell mass.
US Patent Application 2002/0038083 to Houben and Larik, which is incorporated herein by reference, describes methods and apparatus for monitoring blood glucose levels by implanting glucose sensitive living cells, which are enclosed in a membrane permeable to glucose but impermeable to immune system cells, inside a patient. The living cells come from the islets of Langerhans of the pancreas and have been genetically engineered so as to grow on a substrate containing interdigitated electrodes, which serves as a sensor of cellular electrical activity.
U.S. Pat. No. 6,605,039 to Houben and Larik, which is incorporated herein by reference, describes methods and apparatus for monitoring blood glucose levels by implanting glucose sensitive living cells, which are enclosed in a membrane permeable to glucose but impermeable to immune system cells, inside a patient. The heat response of cells from the islets of Langerhans of the pancreas to glucose levels is proposed as a glucose sensor along with measurements of the membrane impedance of pancreatic B-cells as a result of glucose exposure.
U.S. Pat. No. 6,650,919 to Edelberg and Christini, which is incorporated herein by reference, describes methods and apparatus for monitoring physiological or pathophysiological variables in a living organism by implanting tissue or cells capable of carrying out physiological or pathophysiological functions. Particular applications involving the use of cardiac or neuronal tissue to monitor cardiac function and health are discussed.
U.S. Pat. No. 6,368,592 to Colton et al., which is incorporated herein by reference, describes techniques for supplying oxygen to cells in vitro or in vivo by generating oxygen with an oxygen generator that electrolyzes water to oxygen and hydrogen. The oxygen generator may be used to supply oxygen to cells contained in an encapsulating chamber for implanting in the body such as an immunoisolation chamber bounded by a semipermeable barrier layer that allows selected components to enter and leave the chamber. A bioactive molecule may be present with the cells. US Patent Application Publication 2003/0087427 to Colton et al., which is incorporated herein by reference, describes similar techniques.
U.S. Pat. No. 5,443,508 to Giampapa, which is incorporated herein by reference, describes an implantable biological agent delivery system. The system includes a pod adapted for subcutaneous implantation beneath the dermis of the skin. The pod includes a porous surface and has at least one internal chamber which is in fluid communication with the porous surface. The system includes a dome adapted to be detachably secured to the chamber. The dome includes interior chambers, each in fluid communication with the interior of the pod. Prior to implantation, the chambers are loaded with bioactive agents, such as hormones, enzymes, biologic response modifiers, free radical scavengers, or genetically altered cell cultures. Time-release micropumps pump the agents into the interior chambers of the pod for transmission through the porous surfaces into a growth factor-stimulated capillary matrix and then to the bloodstream of the subject. The pod may be removed, refilled, and resecured to the dome upon exhaustion of its contents or upon medical requirement for changes in medication, or may be percutaneously refilled in situ through injection into the dome. The surface of the pod may be treated with one or more vascular growth factors or related biologic molecules.
U.S. Pat. No. 5,614,378 to Yang et al., which is incorporated herein by reference, describes a photobioreactor system for oxygen production for a closed ecological life support system. The photobioreactor is described, among other things, as being useful for converting carbon dioxide to oxygen in an artificial lung.
U.S. Pat. No. 4,721,677 to Clark, Jr., which is incorporated herein by reference, describes an implantable biosensor and method for sensing products, such as hydrogen peroxide, generated from an enzymatic reaction between an analyte, like glucose, and an enzyme in the presence of oxygen. The biosensor is equipped with an enclosed chamber for containing oxygen and can be adapted for extracting oxygen from animal tissue adjacent the container. The biosensor is designed to optically or electrically sense products generated from the enzymatic reaction which serve as a function of the analyte.
U.S. Pat. No. 5,855,613 to Antanavich et al., which is incorporated herein by reference, describes embedding cells in a thin sheet of alginate gel that is then implanted in a body.
U.S. Pat. No. 5,834,005 to Usala, which is incorporated herein by reference, describes immunoisolating cells by placing them in a chamber that is implanted inside the body. In the chamber, the cells are shielded from the immune system by means of a membrane permeable to small molecules such as glucose, oxygen, and the hormone secreted by the cells, but impermeable to cells and antibodies.
U.S. Pat. No. 4,402,694 to Ash et al., which is incorporated herein by reference, describes a body cavity access device for supplying a hormone to a patient. The device includes an implantable housing placed in the body and having an impermeable extracorporeal segment and a semipermeable subcutaneous segment. A hormone source such as live, hormone-producing cells, e.g., pancreatic islet cells, is then removably positioned in the housing to provide a hormone supply to the patient. A sensor can be located within the subcutaneous segment and operably associated with a dispenser to release medication into the housing and to the patient.
U.S. Pat. No. 5,011,472 to Aebischer et al., which is incorporated herein by reference, describes techniques for providing hybrid, modular systems for the constitutive delivery of active factor to a subject and, in some instances, to specific anatomical regions of the subject. The systems include a cell reservoir containing living cells capable of secreting an active agent, which is preferably adapted for implantation within the body of the subject and further includes at least one semipermeable membrane, whereby the transplanted cells can be nourished by nutrients transported across the membrane while at the same time protected from immunological, bacterial, and viral assault. The systems further include a pumping means, which can be implantable or extracorporeal, for drawing a body fluid from the subject into the cell reservoir and for actively transporting the secreted biological factors from the cell reservoir to a selected region of the subject.
U.S. Pat. No. 5,116,494 to Chick et al., which is incorporated herein by reference, describes a device that serves as an artificial pancreas. The device comprises a hollow fiber which is surrounded by islets of Langerhans enclosed in a housing. The islets are suspended in a temperature sensitive matrix which is sufficiently viscous to support islets at a temperature below about 45 degrees C. and sufficiently fluid to enable removal of islet suspension at a temperature above about 45 degrees C. A warm (e.g., 48 degree to 50 degree C. solution) may be flushed through the device to change the physical state of the temperature sensitive matrix from a semi-solid state to a liquefied semi-gel state. The temperature sensitive supporting material is described as enabling long-term maintenance of islet cells in in vitro culture.
U.S. Pat. No. 5,741,334 to Mullon et al., which is incorporated herein by reference, describes an artificial pancreatic perfusion device comprising a hollow fiber having a porosity ranging from about 25 Kd to about 200 Kd. The hollow fiber has one end connected to a blood vessel for receiving blood and a second end connected to a blood vessel for returning the blood. Islets of Langerhans surround the hollow fiber. The hollow fiber and islets are surrounded by a housing comprising a semipermeable membrane having a pore size small enough to offer protection to the islets and host from immune reactive substances.
U.S. Pat. No. 5,702,444 to Struthers et al., which is incorporated herein by reference, describes an implantable artificial endocrine pancreas comprising a reactive body of soft, plastic, biocompatible, porous hydratable material supporting a multiplicity of endocrine pancreatic islets in isolated spaced relationship from each other, and a microporous barrier membrane enveloping and supporting the body, in spaced relationship from the pancreatic islets therein and through which molecules having a molecular weight greater than 60,000 Daltons cannot penetrate.
U.S. Pat. No. 6,630,154 to Fraker et al., which is incorporated herein by reference, describes a composition including at least one glycosaminoglycan, e.g., CIS, at least one perfluorinated substance and at least one alginate, e.g., sodium alginate.
US Patent Application Publication 2004/0109302 to Yoneda et al., which is incorporated herein by reference, describes a plant cultivation method, including cultivating plants with irradiating pulsed light with a period of 2 microseconds to 1 millisecond and a duty ratio of 20% to 70%, using a light emitting diode that emits white light or light of two colors.
U.S. Pat. No. 5,381,075 to Jordan, which is incorporated herein by reference, describes a method for driving an immersed flashing light system to enhance algae growth. The flashing light system includes a plurality of light source elements that are arranged to illuminate the algae. The light source elements are electrically connected to form banks of light source elements. Power is supplied to each bank of light sources in a predetermined sequence at regular intervals to substantially evenly supply each bank of light source elements with a series of power pulses, while maintaining a substantially continuous load on the power supply. The power pulses are substantially half cycles of a square wave.
PCT Publication WO 03/011445 to Monzyk et al., which is incorporated herein by reference, describes a photolytic cell and a photolytic artificial lung incorporated the photolytic cell.
PCT Publication WO 90/15526 to Kertz, which is incorporated herein by reference, describes an integument and related process for the culturing and growing of living organic material. The integument includes a cellule made of a gas-permeable, liquid- and contaminant-impermeable membrane for completely enclosing and sealing the culture from biological contaminants in the ambient environment. The membrane allows gas exchange between the living organic material and the ambient environment to provide enhanced growth and the prevention of contamination.
PCT Publication WO 01/50983 to Vardi et al., and U.S. patent application Ser. No. 10/466,069 in the national phase thereof, which are incorporated herein by reference, describe an implantable device comprising a chamber for holding functional cells and an oxygen generator for providing oxygen to the functional cells. In one embodiment, the oxygen generator comprises photosynthetic cells that convert carbon dioxide to oxygen when illuminated. In another embodiment, the oxygen generator comprises electrodes that produce oxygen by electrolysis. In another embodiment, an implantable chamber is used as part of a system for detecting or monitoring the level of a substance in body fluids. Such a system includes a detector adapted to monitor a property of the functional cells that is correlated with the level of the substance in the medium surrounding the functional cells.
Wu H et al., in “In situ electrochemical oxygen generation with an immunoisolation device,” Ann N Y Acad Sci 875:105-25 (1999), which is incorporated herein by reference, describe an in situ electrochemical oxygen generator which decomposes water electrolytically to provide oxygen to the adjacent planar immunobarrier diffusion chamber. In vitro culture experiments were carried out with beta TC3 cells encapsulated in titanium ring devices. The growth and viability of cells with or without in situ oxygen generation was studied.
Methods for immunoprotection of biological materials by encapsulation are described, for example, in U.S. Pat. Nos. 4,352,883, 5,427,935, 5,879,709, 5,902,745, and 5,912,005, all of which are incorporated herein by reference. The encapsulating material is typically selected so as to be biocompatible and to allow diffusion of small molecules between the cells of the environment while shielding the cells from immunoglobulins and cells of the immune system. Encapsulated beta cells, for example, can be injected into a vein (in which case they will eventually become lodged in the liver) or embedded under the skin, in the abdominal cavity, or in other locations. Fibrotic overgrowth around the implanted cells, however, gradually impairs substance exchange between the cells and their environment. Hypoxia of the cells typically leads to cell death.
PCT Patent Publication WO 01/50983 to Bloch et al., which is incorporated herein by reference, describes methods and apparatus for monitoring physiological variables in a living organism by implanting, inside a patient, functional tissue or cells, which are enclosed in a membrane permeable to glucose and other nutrients but impermeable to immune system cells. In order to maintain a sufficient oxygen supply for the functional cells an oxygen generator comprising photosynthetic cells and a light source is placed inside the membrane. In an application described in the '983 publication, an implantable chamber is used as part of a system for detecting or monitoring the level of a substance in body fluids. Such a system includes a detector adapted to monitor a property of the functional cells that is correlated with the level of the substance in the medium surrounding the functional cells.
PCT Publication WO 04/051774 to Minteer et al., which is incorporated herein by reference, describes bioanodes comprising a quaternary ammonium treated Nation(R) polymer membrane and a dehydrogenase incorporated within the treated Nation(R) polymer. The dehydrogenase catalyzes the oxidation of an organic fuel and reduces an adenine dinucleotide. The ion conducting polymer membrane lies juxtaposed to a polymethylene green redox polymer membrane, which serves to electro-oxidize the reduced adenine dinucleotide.
An article by Khamsi R, entitled, “Microbes Pass Valuable Gas,” Wired News, May 20, 2003, describes the use of microorganisms to power fuel cells, such as by using baker's yeast (aerobic metabolism), algae (photosynthesis), and bacteria.
An article by Parikh et al., entitled, “Role of Spirulina in the control of glycemia and lipidemia in type 2 diabetes mellitus,” J Med Food 2001, Winter 4(4): 193-199, which is incorporated herein by reference, describes a study aimed to evaluate the hypoglycemic and hypolipidemic role of Spirulina. Twenty-five subjects with type 2 diabetes mellitus were randomly assigned to receive Spirulina (study group) or to form the control group. The efficacy of Spirulina (supplementation (2 g/day for 2 months) was determined using the preintervention and postintervention blood glucose levels, glycosylated hemoglobin (HbA(1c)) levels, and lipid profiles of the diabetic subjects. Two-month supplementation with Spirulina resulted in an appreciable lowering of fasting blood glucose and postprandial blood glucose levels.
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Diabetes is a disorder that affects many people and results from the inability of the body to properly utilize and metabolize carbohydrates, particularly glucose. Normally the balance between glucose in the blood and glucose in body tissue cells is maintained by insulin, a hormone produced by the pancreas that controls the transfer of glucose from the blood into body tissue cells. Abnormal levels of glucose in the blood cause many complications and pathologies, leading to premature death in many cases.
Abnormally high levels of blood glucose can be controlled in many cases by the injection of insulin into the body. The amount of insulin to be injected depends upon the level of glucose in the blood, leading to a demand for accurate blood glucose sensors. Since regular monitoring of blood glucose levels allows for better regulation via insulin injections, it is desirable to have a simple and convenient means for monitoring blood glucose levels. Historically, the most common method to determine blood glucose levels was to obtain a small blood sample by piercing the finger and then placing the blood in an analyzer.
To avoid the regular piercing of a finger and to obtain more continuous monitoring of blood glucose levels, implantable glucose sensors have been described. In some cases, implantable sensors have been described that include cells such as transplanted pancreatic cells. These pancreatic cells are described as responding in a manner proportional to blood glucose levels, such that by monitoring the cellular response a blood glucose level can be determined. Several patents and applications using these techniques are discussed hereinbelow.